Abstract

In peripheral nociceptive flexor test, SA4503, (+)-pentazocine, and (+)-3-(hydroxyphenyl)-N-(1-propyl)piperidine, representative ς-receptor agonists, elicited dose-dependent flexor responses. These responses were blocked by ς-receptor antagonists NE-100 or BD1063, but not by pretreatments with antisense oligodeoxynucleotide for ς1 binding protein. The ς-agonists' nociception is attributed to the substance P (SP) release from nociceptor endings through activations of Gα_i1 and phospholipase C (PLC). On the other hand, attomolar doses of neurosteroids such as dehydroepiandrosterone sulfate (DHEAS) and pregnenolone sulfate caused similar nociception, and they were blocked by progesterone (PROG). However, DHEAS nociception was not affected by pertussis toxin, but was completely inhibited by a PLC inhibitor or thapsigargin. Although the nociception by lower doses of DHEAS was abolished by diphenhydramine (DPH), H1 antagonist, there were dose-dependent responses by high doses of DHEAS in the presence of DPH. The responses by DHEAS in the presence of DPH were blocked by NE-100, and those by (+)-pentazocine were blocked by PROG. All these findings suggest that two novel types of neurosteroid receptors exist, neuronal NS1/ς-type, which mediates activation of Gα_i1 by neurosteroids and ς-agonists, followed by SP release from nociceptor endings; and NS2 type, which mediates histamine release from mast cells by very low doses of neurosteroids.